The Coulombe lab is an open science ecosystem where basic scientists and clinical researchers, from the academic or private sectors, collaborate to i) characterize molecular defects that cause rare genetic diseases, ii) identify biomarkers to pre-diagnose patient phenotypes, and iii) discover drugs that will ultimately generate affordable medicines for patients everywhere.
Unraveling the molecular basis of novel forms of hypomyelinating leukodystrophies (CIHR, Lead G. Bernard MUHC).
A biomarker discovery pipeline for precision medicine (Government of Quebec/IRCM, Lead B. Coulombe IRCM).
A patient-derived iPSC platform of disease relevant cell models for biological studies (ALS Canada and Brain Canada, Lead G. Rouleau MNIH).
Deciphering breast cancer HER2-negativity with regard to HER2-targeted therapy (CIHR, Lead F. Durocher, U Laval).
A machine learning approach to decipher protein-protein interactions in human plasma (IVADO and Genome Québec, Lead B. Coulombe IRCM).
Modulation of protein interactions by the Superoxide Dismutase 1 (SOD1) (supported by Atomwise Inc, Lead B. Coulombe IRCM).
The soluble fragment of neuroligin-1 as a blood biomarker of prodromal Alzheimer’s disease (Weston Brain Institute, Lead J. Brouillette HSCM).
Characterization of neuro-muscular junctions in ALS patients (ALS Canada, Lead R. Robitaille, U Montreal).
Reducing the activity of the phosphatase STEP to improve memory performance during aging (CIHR, Lead J. Brouillette HSCM).
Screening of chemical compounds that correct assembly defects of RNA polymerase III carrying a leukodystrophy-causing mutation (Leukodystrophy’s Foundation, Lead B. Coulombe IRCM).
OUR FLAGSHIP PROJECTS AND TECHNOLOGIES
THE RARE DISEASE CELL MAP
Affinity Purification coupled with Mass Spectrometry (AP-MS) and Proximity-Dependent Protein Identification (BioID)
Proteins rarely work alone, they rather associate with other proteins to exert their function. The Rare Disease Cell Map is a comprehensive repository of protein-protein interactions formed by rare disease-causing gene products and their modulation in response to causative mutations. Some data are already available on the Open for Rare website at OpenforRare.com
A BIOMARKER DISCOVERY PIPELINE FOR PRECISION MEDICINE
Quantitative proteomics (TMT, PAC-qMS)
Quantitative proteomics is a methodology of choice to discover biomarkers and monitor their levels in various samples. We privilege Tandem Mass Tag (TMT) to perform unbiased identification of proteins that are differentially expressed in various samples (discovery proteomics). Protein Affinity Capture coupled to quantitative Mass Spectrometry (PAC-qMS) is rather used to precisely quantify levels of a selected protein and posttranslational modifications in various samples.
Phage Display Peptide Library Screening
Identification of peptides that bind to specific proteins and protein domains is a powerful tool in biomedical research. Smith and Winter were awarded the 2018 Nobel Prize in Chemistry for the phage display of peptides and antibodies. Notably, binding of peptides to a protein of interest can either impair its activity or stabilize it interactions with other proteins. As a consequence, phage display can be a useful tool in the drug discovery process.
PROTEIN CHARACTERIZATION USING PEPTIDES AND ANTIBODIES
PUBLICATIONS (past 3 years)
Cloutier P, Poitras C, Faubert D, Bouchard A, Blanchette M, Gauthier MS, Coulombe B. Upstream ORF-Encoded ASDURF Is a Novel Prefoldin-like Subunit of the PAQosome. J Proteome Res. 2020 Jan 3;19(1):18-27.
Ben Djoudi Ouadda A, Gauthier MS, Susan-Resiga D, Girard E, Essalmani R, Black M, Marcinkiewicz J, Forget D, Hamelin J, Evagelidis A, Ly K, Day R, Galarneau L, Corbin F, Coulombe B, Çaku A, Tagliabracci VS, Seidah NG. Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor). Arterioscler Thromb Vasc Biol. 2019 Oct;39(10):1996-2013.
Choquet K, Pinard M, Yang S, Moir RD, Poitras C, Dicaire MJ, Sgarioto N, Larivière R, Kleinman C, Willis IM, Gauthier MS, Coulombe B, Brais B. The leukodystrophy mutation Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis. Mol Brain. 2019 Jun 20;12(1):59.
Choquet K, Forget D, Meloche E, Dicaire MJ, Bernard G, Vanderver A, Schiffmann R, Fabian MR, Teichmann M, Coulombe B, Brais B, Kleinman CL. Leukodystrophy-associated POLR3A mutations down-regulate the RNA polymerase III transcript and important regulatory RNA BC200. J Biol Chem. 2019 Mar 21. pii: jbc.RA118.006271.
Gauthier MS, Cloutier P, Coulombe B. Role of the PAQosome in Regulating Arrangement of Protein Quaternary Structure in Health and Disease. Adv Exp Med Biol. 2018;1106:25-36. doi: 10.1007/978-3-030-00737-9_3.
Gauthier MS, Awan Z, Bouchard A, Champagne J, Tessier S, Faubert D, Chabot K, Garneau PY, Rabasa-Lhoret R, Seidah NG, Ridker PM, Genest J, Coulombe B. Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics. J Clin Lipidol. 2018 Jul - Aug;12(4):1027-1038.
Mendes MI, Gutierrez Salazar M, Guerrero K, Thiffault I, Salomons GS, Gauquelin L, Tran LT, Forget D, Gauthier MS, Waisfisz Q, Smith DEC, Simons C, van der Knaap MS, Marquardt I, Lemes A, Mierzewska H, Weschke B, Koehler W, Coulombe B, Wolf NI, Bernard G. Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy. Am J Hum Genet. 2018 Apr 5;102(4):676-684.
Lavallée-Adam M, Cloutier P, Coulombe B, Blanchette M. Functional 5' UTR motif discovery with LESMoN: Local Enrichment of Sequence Motifs in biological Networks. Nucleic Acids Res. 2017 Oct 13;45(18):10415-10427.
Cloutier P, Poitras C, Durand M, Fiola-Masson E, Bouchard A, Faubert D, Chabot B,
Coulombe B. R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein. Nat Commun. 2017;8:15615.
Choquet K, Yang S, Moir RD, Forget D, Larivière R, Bouchard A, Poitras C, Sgarioto N, Dicaire MJ, Noohi F, Kennedy TE, Rochford J, Bernard G, Teichmann M, Coulombe B, Willis IM, Kleinman CL, Brais B. Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation. Mol Brain. 2017 Apr 13;10(1):13.
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